Methods and compositions for prevention of angioproliferation

Abstract

The invention provides pharmaceutical compositions comprising Porphyromonas gingivalis protease and hemagglutinin polypeptides that have anti-angiogenic activity and methods for their use.

1 . A composition for the treatment, prevention, or amelioration of an angioproliferitive condition comprising a pharmaceutically effective amount of a substantially purified  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide,  Porphyromonas gingivalis  hemagglutinin polypeptide, or a combination thereof, wherein the polypeptide has anti-angiogenic activity, and a pharmaceutically acceptable excipient.  
     
     
         2 . The composition of claim. 1, wherein the polypeptide is selected from the group consisting of rgpA, rgpB, kgp, hag, prtT and tla polypeptides.  
     
     
         3 . The composition of  claim 2 , wherein the polypeptide has at least about 90% sequence identity with a rgpA, rgpB, kgp, hag, prtT or tla polypeptide and wherein the polypeptide has anti-angiogenic activity.  
     
     
         4 . The composition of  claim 2 , wherein the polypeptide is a biologically functional homolog, or isoform of a rgpA, rgpB, kgp, hag, prtT or tla polypeptide.  
     
     
         5 . The composition of  claim 1 , wherein the polypeptide is a fragment of a  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide, or  Porphyromonas gingivalis  hemagglutinin polypeptide, and wherein the fragment has anti-angiogenic activity.  
     
     
         6 . The composition of  claim 5 , wherein the fragment is HA2.  
     
     
         7 . The composition of  claim 1 , wherein the angioproliferative condition is carcinoma, sarcoma, melanoma, benign tumor, ocular retinopathy, retrolental fibroplasias, psoriasis, angiofibromas, endometriosis, hemangioma, rheumatoid arthris, Osler Webber Syndrome, myocardial angiogenesis, telangiectasia, hemophiliac joints, wound granulation, intestinal adhesions, post-surgery adhesions, arteriosclerosis, scleroderma, hypertrophic scars, cat scratch disease,  Helicobacter pylori  ulcers, capillary proliferation within atherosclerotic plaque, or a combination thereof.  
     
     
         8 . A method for the treatment, prevention, or amelioration of an angioproliferative condition comprising administering a pharmaceutically effective amount of a  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide,  Porphyromonas gingivalis  hemagglutinin polypeptide, or a combination thereof wherein the polypeptide has anti-angiogenic activity, to a patient in need thereof whereby the angioproliferative condition is treated, prevented or ameliorated.  
     
     
         9 . The method of  claim 8 , wherein the polypeptide is selected from the group co-ng of rgpA, rgpB, kgp, hag, prtT and tla polypeptides.  
     
     
         10 . The method of  claim 8 , wherein the polypeptide has at least about 90% sequence identity with a rgpA, rgpB, kgp, hag, or tla polypeptide and wherein the polypeptide has anti-angiogenic activity.  
     
     
         11 . The method of  claim 8 , wherein the polypeptide is a fragment of a  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide, or a  Porphyromonas gingivalis  hemagglutinin polypeptide, ad wherein the fragment has anti-angiogenic activity.  
     
     
         12 . The method of  claim 11 , wherein the polypeptide fragment is HA2.  
     
     
         13 . The method of  claim 8 , wherein the angioproliferative condition is carcinoma, sarcoma, melanoma, benign tumor, ocular retinopathy, retrolental fibroplasias, psoriasis, angiofibromas, endometriosis, hemangioma, rheumatoid arthritis, Osler Webber Syndrome, myocardial angiogenesis, telangiectasia, hemophiliac joints, wound granulation, intestinal adhesions, post-surgery adhesions, atherosclerosis, scleroderma, hypertrophic scars, cat scratch disease,  Helicobacter pylori  ulcers, capillary proliferation within atherosclerotic plaque, or a combination thereof.  
     
     
         14 . The method of  claim 8 , wherein the method comprises contacting a vasculature supplying a biological structure affected by the angioproliferative condition with the polypeptide.  
     
     
         15 . The method of  claim 14 , wherein the polypeptide is contacted with a basolateral surface of the vasculature.  
     
     
         16 . A method for potentiating effects of a chemotherapeutically effective agent comprising administering to a patient: 
 (a) a  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptid,  Porphyromonas gingivalis  hemagglutinin polypeptide, or a combination thereof, wherein the polypeptide disrupts cell-cell adhesion, cell-matrix adhesion, or both; and    (b) a chemotherapeutically effective agent,    whereby effects of a chemotherapeutically effective agent are potentiated.    
     
     
         17 . The method of  claim 16 , wherein the polypeptide is selected from the group consisting of rgpA, rgpB, kgp, hag, prtT and tla polypeptides.  
     
     
         18 . The method of  claim 17 , wherein the polypeptide has at least about 900% sequence identity with a rgpA, rgpB, kgp, hag, or tla polypeptide, and wherein the polypeptide has anti-angiogenic activity.  
     
     
         19 . The method of  claim 16 , wherein the polypeptide is a fragment of  Porphyromonas gingivalis  arginine specific cystine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide, or  Porphyromonas gingivalis  hemagglutinin polypeptide, and wherein the fragment has proteinase activity.  
     
     
         20 . The composition of  claim 19 , wherein the polypeptide fragment is HA2.  
     
     
         21 . A method for preventing the formation of new vasculature required for implantation or sustenance of a fertilized an ovum comprising: 
 administering a  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide,  Porphyromonas gingivalis  hemagglutinin polypeptide, or a combination thereof to a mammal, wherein the polypeptide has anti-angiogenic activity, whereby the formation of new vasculature required for implantation or sustenance of a fertilized mammalian ovum is prevented.    
     
     
         22 . The method of  claim 21 , wherein the polypeptide is selected from the group consisting of rgpA, rgpB, kgp, hag, prtT and tla polypeptides.  
     
     
         23 . The method of  claim 22 , wherein the polypeptide has at least about 90% sequence identity with a rgpA, rgpB, kgp, hag, prtT, or ta polypeptide and wherein the polypeptide has anti-angiogenic activity.  
     
     
         24 . The method of  claim 21 , wherein the polypeptide is a fragment of a  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide, or  Porphyromonas gingivalis  hemagglutinin polypeptide, and wherein the fragment has anti-angiogenic activity.  
     
     
         25 . The method of  claim 24 , wherein the polypeptide fragment is HA2.  
     
     
         26 . A pharmaceutical composition for facilitating passage of a compound through a blood-brain barrier comprising a pharmaceutically effective amount of a substantially purified  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide, a  Porphyromonas gingivalis  hemagglutinin polypeptide, or a combination thereof, and a pharmaceutically acceptable excipient.  
     
     
         27 . The pharmaceutical composition of  claim 26  further including a compound to be passed through the blood-brain barrier.  
     
     
         28 . A method delivering a compound through a blood-brain barrier of a patient comprising administering a pharmaceutically effective amount of a  Porphymonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide,  Porphyromonas gingivalis  hemagglutinin polypeptide, or a combination thereof and the compound, whereby the compound is passed through the blood-brain barrier.  
     
     
         29 . The method of  claim 28 , wherein the polypeptide is selected from the group consisting of rgpA, rgpB, kgp, hag, prtT and tla polypeptides.  
     
     
         30 . The method of  claim 29 , wherein the polypeptide has at least about 90% sequence identity with a rgpA, rgpB, kgp, hag, prtT or tla polypeptide and wherein the polypeptide has anti-angiogenic activity.  
     
     
         31 . The method of  claim 28 , wherein the polypeptide is a foment of a  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide, or a  Porphyromonas gingivalis  hemagglutinin polypeptide, and wherein the fragment has anti-angiogenic activity.  
     
     
         32 . The method of  claim 31 , wherein the polypeptide fragment is HA2.  
     
     
         33 . A method of degrading a tumor comprising: 
 administering a pharmaceutically effective amount of a  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide,  Porphyromonas gingivalis  hemagglutinin polypeptide, or a combination thereof to a patient having a tumor, wherein the polypeptide degrades cell-cell bonds, cell-matrix bonds, or both cell-cell bonds and cell-matrix bonds of the tumor, whereby the tumor is degraded.    
     
     
         34 . The method of  claim 33  wherein the polypeptide is selected from the group consisting of rgpA, rgpB, kgp, hag, prtT and tla polypeptides.  
     
     
         35 . The method of  claim 34  wherein the polypeptide has at least about 90% se ce identity with a rgpA, rgpB, kgp, hag, prtT or tla polypeptide and wherein the polypeptide has anti-angiogenic activity.  
     
     
         36 . The method of  claim 33  wherein the polypeptide is a fragment of a  Porphyromonas gingivalis  arginine specific cysteine protease polypeptide,  Porphyromonas gingivalis  lysine specific cysteine protease polypeptide, or  Porphyromonas gingivalis  is hemagglutinin polypeptide, and wherein the fragment has anti-angiogenic activity.  
     
     
         37 . The method of  claim 36  wherein the polypeptide fragment is HA2.